Pyrrolotriazine compounds useful as kinase inhibitors and methods of treating kinase-associated conditions therewith

ABSTRACT

The invention relates to at least one pyrrolotriazine derivative, at least one pharmaceutical composition comprising at least one pyrrolotriazine derivative, and at least one method of using at least one pyrrolotriazine derivative to treat at least one kinase associated condition.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional application Ser.No. 60/696,215, filed Jul. 1, 2005, the contents of which are herebyincorporated herein by reference.

FIELD OF THE INVENTION

Disclosed herein is at least one pyrrolotriazine derivative, at leastone pharmaceutical composition comprising at least one pyrrolotriazinederivative described herein, and at least one method of using at leastone pyrrolotriazine derivative disclosed herein for treating at leastone kinase associated condition.

BACKGROUND OF THE INVENTION

Hyperproliferative diseases, such as, for example, cancer are generallycharacterized by uncontrolled cellular proliferation and/or disruptionin programmed cell death. The loss of a cell's ability to controlcellular proliferation is often caused by genetic damage to the cellularpathways responsible for regulating cellular functions, including butnot limited to, for example, metabolism, cell cycle progression, celladhesion, vascular function, apoptosis, and angiogenesis. As a result,one approach to treating hyperproliferative diseases has involvedtargeting at least one protein involved in regulating these cellularfunctions.

The protein kinases are at least one class of proteins that has beenidentified as playing an important role in regulating cellularfunctions. Indeed, many diseases are associated with abnormal cellularresponses triggered by protein kinase-mediated events. Such diseasesinclude but are not limited to autoimmune diseases, bone diseases,inflammatory diseases, metabolic diseases, neurological andneurodegenerative diseases, cancer, cardiovascular diseases, allergiesand asthma, Alzheimer's disease, and hormone related diseases.

The protein kinases are a large and diverse group of enzymes that aredivided into groups based on the particular amino acids(serine/threonine, tyrosine, lysine and histidine) that a particularkinase targets. For example, receptor and non-receptor tyrosine kinasestarget tyrosine kinase and cyclin dependent kinases (CDKs) and mitogenactivated protein kinases (MAPKs) target both tyrosine andserine/threonine.

Exemplary protein kinases, include, but are not limited to, for example,receptor tyrosine kinases (RTKs), such as, for example, growth factorsincluding, for example, type III receptor tryrosine kinase (Flt3);non-receptor tyrosine kinases, such as, for example, Src kinasesincluding, for example, Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk,Btk kinases, Csk kinases, ZAP70 kinases, and Kak kinases;serine/threonine kinases, such as, for example, p90 ribosomal S6 kinases(RSK), including, for example, RSK1/p90Rsk, RSK2, RSK3, and RSK4,checkpoint protein kinases, including, for example, CHK1 and CHK2,AURORA kinases, including, for example, aurora-A, aurora-B, andaurora-C, and Glycogen synthase kinase 3 (GSK3); cyclin dependentkinases (CDKs) including, for example, CDK1, CDK2, CDK4, CDK5, CDK6, CDK7, and cell division control 2 protein (CDC2); and mitogen-activatedprotein kinases (MAPKs), such as, for example, mitogen-activated proteinkinase 1 (ERK), MAPK3, MAPK7, mitogen-activated protein kinase 8 (JNK1),mitogen-activated protein kinase 14 (p38 alpha), MAPK 10, JNK 3 alphaprotein kinase, stress-activated protein kinase JNK 2, and MAPK 14.

More recently, the Aurora kinases were discovered to be involved in thegrowth of various types of cancer cells, and as a result are beingtargeted to develop potential cancer treatments. Accordingly, effortshave been undertaken to develop Aurora kinase inhibitors that aretherapeutically effective against cancer cells.

SUMMARY OF THE INVENTION

Disclosed herein are compounds of Formula (I):

-   -   (I)        or a pharmaceutically acceptable salt thereof, wherein

-   Q¹ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

-   R¹ is H, —NR⁶C(═O)R⁷, —OR⁷, or —C(═O)NR⁷R⁸;

-   Q² is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

-   R² is H, alkyl, substituted alkyl, hydroxy (—OH), alkoxy, halogen,    haloalkyl, haloalkoxy, oxo, aryloxy, arylalkyl, arylalkyloxy,    alkanoyl, substituted alkanoyl, alkanoyloxy, amino, aminoalkyl,    substituted aminoalkyl, alkylamino, substituted alkylamino,    hydroxyalkyl, disubstituted amino, amide, substituted amide,    carbamate, substituted carbamate, ureido, cyano, sulfonamide,    substituted sulfonamide, alkylsulfone, heterocycloalkyl, substituted    heterocycloalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,    substituted cycloalkenyl, cycloalkylalkyl, cycloalkylalkoxy, nitro,    thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy,    alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, —NR⁶(C═O)R⁹, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted    aryl, heteroaryl, substituted heteroaryl, heteroaryloxy,    arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl,    heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, heterocycle,    substituted heterocycle, alkylcarbonyl, heteroalkyl, substituted    heteroalkyl, heteroalkenyl, substituted heteroalkenyl,    heteroalkynyl, substituted heteroalkynyl, arylamino, arylalkylamino,    alkanoylamino, arylamino, arylalkanoylamino, arylthio,    arylalkylthio, arylsulfonyl, arylalkylsulfonyl, alkylsulfonyl,    arylcarbonylamino, or alkylaminocarbonyl;

-   R³, R⁴, and R⁵ are independently selected from H, alkyl, substituted    alkyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, alkanoyl,    substituted alkanoyl, amino, aminoalkyl, substituted aminoalkyl,    alkylamino, substituted alkylamino, amide, substituted amide,    carbamate, ureido, cyano, sulfonamide, substituted sulfonamide,    alkylsulfone, cycloalkyl, substituted cycloalkyl, nitro, thio,    thioalkyl, alkylthio, disubstituted amino, alkylsulfonyl,    alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl,    —NR⁶(C═O)R⁹, alkenyl, substituted alkenyl, alkynyl, substituted    alkynyl, and alkylcarbonyl.

-   R⁶ is H, lower alkyl, or substituted lower alkyl;

-   R⁷ and R⁸ are independently selected from H, alkyl, substituted    alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,    heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted    heterocycloalkyl, heteroalkyl, substituted heteroalkyl,    heteroalkenyl, substituted heteroalkenyl, hetroalkynyl, or    substituted heteroalkynyl; and

-   R⁹ is H, alkyl, substituted alkyl, alkoxy, aminoalkyl, substituted    aminoalkyl, alkylamino, substituted alkylamino, aryl, or substituted    aryl.

Further described herein is at least one pharmaceutical compositioncomprising at least one compound in accordance with Formula (I),optionally at least one pharmaceutically-acceptable carrier and/ordiluent, and optionally at least one other anti-cancer agent.

Even further described herein is at least one method for treating atleast one proliferative disease comprising administering to a patient inneed thereof an effective amount of at least one compound according toFormula (I), optionally administering either simultaneously orsequentially at least one other anti-cancer agent, and optionallyadministering either simultaneously or sequentially at least one otheranti-cancer treatment.

Yet even further described herein is at least one Formula (I) compoundselected from: (i)N-[4-({4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f1[1,2,4]triazin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide;N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-{[3-(methyloxy)phenyl]sulfanyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine;N-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}sulfanyl)phenyl]acetamide;3-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}sulfanyl)-N-methylbenzamide;N-(5-methyl-1H-pyrazol-3-yl)-2-(phenylsulfanyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine;andN-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)sulfanyl)phenyl)benzamide;and (ii) pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The features and advantages of the invention may be more readilyunderstood by those of ordinary skill in the art upon reading thefollowing detailed description. It is to be appreciated that certainfeatures of the invention that are, for clarity reasons, described aboveand below in the context of separate embodiments, may also be combinedto form a single embodiment. Conversely, various features of theinvention that are, for brevity reasons, described in the context of asingle embodiment, may also be combined so as to form sub-combinationsthereof.

Unless specifically stated otherwise herein, references made in thesingular may also include the plural. For example, “a” and “an” mayrefer to either one, or one or more.

Embodiments identified herein as exemplary or preferred are intended tobe illustrative and not limiting.

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

The definitions set forth herein take precedence over definitions setforth in any patent, patent application, and/or patent applicationpublication incorporated herein by reference.

Definitions of terms used in describing the invention are set forthhereinbelow. Unless otherwise indicated, the initial definition providedfor a group or term applies each time such group or term is usedindividually or as part of another group.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds.

The terms “alkyl” and “alk” refer to a straight chain or branched chainsaturated hydrocarbon radical containing from 1 to 12 carbon atoms andpreferably from 1 to 6 carbon atoms. Exemplary “alkyl” and/or “alk”groups include, but are not limited to, for example, methyl, ethyl,propyl, isopropyl, 1-methylpropyl, n-butyl, t-butyl, isobutyl, pentyl,hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, diethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, and dodecyl.

The term “substituted alkyl” refers to an alkyl group substituted withat least one substituent at any available and substitutable position.Exemplary substituents include, but are not limited to, for example,hydrogen, alkyl, hydroxy (—OH), alkoxy, halogen, haloalkyl, haloalkoxy,oxo, aryloxy, arylalkyl, arylalkyloxy, alkanoyl, substituted alkanoyl,alkanoyloxy, amino, aminoalkyl, substituted aminoalkyl, alkylamino,substituted alkylamino, hydroxyalkyl, disubstituted amino, amide,substituted amide, carbamate, substituted carbamate, ureido, cyano,sulfonamide, substituted sulfonamide, alkylsulfone, heterocycloalkyl,substituted heterocycloalkyl, cycloalkyl, substituted cycloalkyl,cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio,alkylsulfonyl, alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy,carbamoyl, —NR⁶(C═O)R⁹, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heteroaryloxy, arylheteroaryl, arylalkoxycarbonyl,heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl,heterocycle, substituted heterocycle, alkylcarbonyl, heteroalkyl,substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl,heteroalkynyl, substituted heteroalkynyl, arylamino, arylalkylamino,alkanoylamino, arylamino, arylalkanoylamino, arylthio, arylalkylthio,arylsulfonyl, arylalkylsulfonyl, arylcarbonylamino, andalkylaminocarbonyl.

The term “lower alkyl” refers to an alkyl group containing from 1 to 4carbon atoms. It is of import to note that although the term “loweralkyl” is encompassed within the definition of “alkyl”, the usage of theterm “lower alkyl” is not intended to limit the definition of the term“alkyl” either explicitly or implicitly to a straight- or branched-chainsaturated hydrocarbon radical containing from 5 to 7 carbon atoms.Exemplary lower alkyl groups include, but are not limited to, forexample, methyl; ethyl; propyl; isopropyl; n-butyl; t-butyl; isobutyl;pentyl; and isopentyl

The term “substituted lower alkyl” refers to a lower alkyl substitutedat any available and substitutable position with at least one alkyl,substituted alkyl, or substituent described above in defining the term“substituted alkyl” as an exemplary alkyl substituent.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbonrings having from 6 to 12 carbon atoms in the ring portion. Exemplaryaryl groups include but are not limited to, for example, phenyl;naphthalenyl; biphenyl; and diphenyl groups. When two aromatic rings arepresent, the aromatic rings of the aryl group may either be joined at asingle point (e.g., biphenyl), or be fused (e.g., naphthalenyl). Theterm “aryl” also includes rings having a second, third, fourth, or fifthring fused thereto that is a heterocyclo, substituted heterocyclo,heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl,or substituted cycloalkyl, provided in such cases the point ofattachment is to the aryl portion of the ring system. The term “aryl”further includes rings having a second, third, fourth, or fifth ringattached to the ring or ring system in a spiro fashion, wherein suchsecond, third, fourth, or fifth ring is a heterocyclo, substitutedheterocyclo, heteroaryl, substituted heteroaryl, aryl, substituted aryl,cycloalkyl, or substituted cycloalkyl.

The term “substituted aryl” refers to an aryl substituted with at leastone substituent at any available and substitutable ring position, orwhere valence allows on any rings fused or attached thereto. Exemplarysubstituents include, but are not limited to, for example, hydrogen;alkyl, substituted alkyl, hydroxy (—OH), alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxyarylthio, halogen, haloalkyl, haloalkoxy, aryl,aryloxy, arylalkyl, arylalkyloxy, alkanoyl, substituted alkanoyl,alkanoylamino, amino, aminoalkyl, substituted aminoalkyl, alkylamino,substituted alkylamino, disubstituted amino, aminocarbonyl, arylamino,arylalkylamino, arylalkoxy, ureido, cyano, sulfonamide, substitutedsulfonamide, heterocycloalkyl, substituted heterocycloalkyl,heterocycloalkylalkyl, cycloalkyl, substituted cycloalkyl,cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio,alkylsulfonyl, alkylsulfinyl, carboxy, carboxyalkyl, carboxyalkoxy,alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, arylsulfonylamino, arylalkenyl,aryloxycarbonyl, arylthio, arylthioalkyl, arylalkylthio, sulfonic acid,heteroaryl, substituted heteroaryl, heteroarylthio, heteroaryloxy,heteroarylalkenyl, heteroarylheteroaryl, heteroarylalkylthio,heteroaryloxyalkyl, alkylcarbonyl, aminocarbonylaryl,aminocarbonylalkyl, arylazo, alkoxycarbonylalkoxy, arylcarbonyl,alkylaminocarbonyl, aminoalkylcarbonyl, arylaminocarbonyl,alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfonyl, heteroarylsulfonyl,heterocycloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, andarylsulfonylaminocarbonyl.

The term “substituted phenyl” refers to a phenyl substituted with atleast one substituent described above as a “substituted aryl”substituent.

The terms “aryloxy”, “arylamino”, “arylalkylamino”, “arylthio”,“arylalkanoylamino”, “arylsulfonyl”, “arylalkoxy”, “arylsulfinyl”,“arylheteroaryl”, “arylalkylthio”, “arylcarbonyl”, “arylalkenyl”, or“arylalkylsulfonyl” refer to an aryl or substituted aryl bonded to anoxygen; an amino; an alkylamino; a thio; an alkanoylamino; a sulfonyl;an alkoxy; a sulfinyl; a heteroaryl or substituted heteroaryl; analkylthio; a carbonyl; an alkenyl; or an alkylsulfonyl, respectively

The term “arylsulfonylaminocarbonyl” refers to an arylsulfonyl bonded toan aminocarbonyl.

The terms “aryloxyalkyl”, “aryloxycarbonyl” or “aryloxyaryl” refer to anaryloxy bonded to an alkyl or substituted alkyl; a carbonyl; or an arylor substituted aryl, respectively.

The term “arylalkyl” refers to an alkyl or substituted alkyl in which atleast one of the hydrogen atoms bonded to at least one of the carbonatoms is replaced with an aryl or substituted aryl. Typical arylalkylsinclude, but are not limited to, for example, benzyl,2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, and2-naphthophenylethan-1-yl.

The term “arylalkyloxy” refers to an arylalkyl bonded through an oxygenlinkage (—O-arylalkyl).

The terms “arylthioalkyl” or “arylsulfinylalkyl” refer to an arylthio oran arylsulfinyl, respectively, bonded to an alkyl or substituted alkyl.

The term “heteroaryl” refers to aromatic cyclic groups, such as, forexample, 5- to 6-membered monocyclic, 7- to 11-membered bicyclic, or 10-to 16-membered tricyclic ring systems having at least one heteroatom inat least one carbon atom-containing ring. The carbon atom-containingring may contain 1, 2, 3, or 4 heteroatom(s) selected from nitrogen,oxygen, and/or sulfur. The heteroaryl group may be attached to anothermoiety at any available point of attachment.

Exemplary monocyclic heteroaryl groups include, but are not limited to,for example, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl,thiazolyl, isoxazolyl, thiazolyl, pyridyl

pyridazinyl

pyrimidinyl

pyrazinyl

and triazinyl. Unless reference is made to a specific point ofattachment, e.g., as in pyrid-2-yl, pyridazin-3-yl, it is intended thatsuch heteroaryl groups can be bonded to another moiety at any availablepoint of attachment.

Exemplary bicyclic heteroaryl groups include, but are not limited to,for example, benzothiazolyl, benzoxazolyl, benzoxadiazolyl,benzothienyl, quinolinyl, chromenyl, indolyl, indazolyl, isoquinolinyl,benzimidazolyl, benzopyranyl, benzofuryl, benzofurazanyl, benzopyranyl,cinnolinyl, quinoxalinyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),and triazinylazepinyl.

The term “substituted heteroaryl” refers to a heteroaryl substituted atany available and substitutable ring position, or where valence allowson any rings fused or attached thereto, with at least one aryl,substituted aryl, or substituent described above in defining the term“substituted aryl” as an exemplary aryl substituent.

The terms “heteroaryloxy”, “heteroarylalkenyl”, “heteroarylheteroaryl”,“heteroarylalkyl”, “heteroarylalkoxy”, “heteroarylthio”,“heteroarylsulfonyl”, or “heteroarylalkylthio” refer to a heteroaryl orsubstituted heteroaryl bonded to an oxygen; an alkenyl or substitutedalkenyl; a heteroaryl or substituted heteroaryl; an alkyl or substitutedalkyl; an alkoxy; a thio; a sulfonyl; or an alkylthio, respectively.

The term “heteroaryloxyalkyl” refers to a heteroaryloxy bonded to analkyl or substituted alkyl.

The term “cycloalkyl” refers to a fully saturated or partiallyunsaturated cyclic hydrocarbon group containing from 1 to 3 rings and 3to 8 carbons per ring. Exemplary cycloalkyls include, but are notlimited to, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.A cycloalkyl ring may have a carbon ring atom replaced with a carbonylgroup (C═O). Cycloalkyls include such rings having a second or thirdring fused thereto that is a heterocyclo, substituted heterocyclo,heteroaryl, substituted heteroaryl, aryl or substituted aryl, providedthat in such cases the point of attachment is to the cycloalkyl portionof the ring system. The term “cycloalkyl” also includes rings having asecond or third ring attached to the ring or ring system in a spirofashion.

The term “substituted cycloalkyl” refers to a cycloalkyl substitutedwith at least one substitutent, preferably 1 to 4 substituents, morepreferably 1 to 2 substituents, at any available point of attachment oneither the cycloalkyl ring, or where valence allows on any rings fusedor attached thereto. Exemplary substituents include, but are not limitedto, for example, alkyl, substituted alkyl, and the substituentsdescribed in defining the term “substituted alkyl” as exemplary alkylsubstituents.

Exemplary cycloalkyls include but are not limited to, for example,

The term “heterocycloalkyl” refers to a saturated or unsaturatedcycloalkyl in which one or more carbons (and any associated hydrogenatoms) are independently replaced with at least one heteroatom selectedfrom O and N.

The term “substituted heterocycloalkyl” refers to a heterocycloalkylsubstituted at any available and substitutable ring position with atleast one alkyl, substituted alkyl, or substituent described above indefining the term “substituted alkyl” as an exemplary alkyl substituent.

The terms “heterocycloalkylalkyl” or “heterocycloalkylsulfonyl” refer toa heterocycloalkyl or substituted heterocycloalkyl bonded to an alkyl orsubstituted alkyl or a sulfonyl, respectively.

The terms “heterocycle”, “heterocyclic”, and “heterocyclo” refer tofully saturated or partially or fully unsaturated, aromatic ornonaromatic cyclic groups that are, for example, 4 to 7 memberedmonocyclic, 7 to 111 membered bicyclic, or 10 to 15 membered tricyclicring systems that have at least one heteroatom in at least one carbonatom containing ring. Each ring of the heterocycle, heterocyclic, orheterocyclo containing a heteroatom may have 1, 2 or 3 heteroatomsselected from N, O, and S, where the N and/or S heteroatom(s) mayoptionally be oxidized and the N heteroatom(s) may optionally bequaternized. The heterocycle, heterocyclic, or heterocyclo may beattached to the remainder of the molecule via any available heteroatomor carbon atom. Heterocycle, heterocyclic, or heterocyclo include suchrings having a second or third ring fused thereto that is a heterocyclo,substituted heterocyclo, heteroaryl, substituted heteroaryl, aryl,substituted aryl, cycloalkyl, or substituted cycloalkyl, provided insuch cases the point of attachment is to the heterocycle, heterocyclic,or heterocyclo portion of the ring system. The terms “heterocycle”,“heterocyclic”, or “heterocyclol” also include rings having a second orthird ring attached to the ring or ring system in a spiro fashion,wherein such second or third ring is a heterocyclo, substitutedheterocyclo, heteroaryl, substituted heteroaryl, aryl, substituted aryl,cycloalkyl, or substituted cycloalkyl.

Exemplary monocyclic heterocycles, heterocyclics, or heterocyclosinclude, but are not limited to, for example, pyrrolidinyl, pyrrolyl,indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, homopiperazinyl,2-oxohomopiperazinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl,4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl,thiiranyl, triazinyl, and triazolyl.

Exemplary bicyclic heterocycles, heterocyclics, or heterocyclos include,but are not limited to, for example, 2,3-dihydro-2-oxo-1H-indolyl,benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl,quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl] orfuro[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl,benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,dihydrobenzopyranyl, indolinyl, indazolyl, isochromanyl, isoindolinyl,naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, andthienothienyl.

The terms “substituted heterocycle”, “substituted heterocyclic”, or“substituted heterocyclo” refer to a heterocycle, heterocyclic, orheterocyclo, respectively, substituted at any available point ofattachment, or where valence allows on any rings fused or attachedthereto, with at least one alkyl, substituted alkyl, or substituentdescribed above in defining the term “substituted alkyl” as an exemplaryalkyl substituent.

The terms “heteroalkyl”, “heteroalkenyl”, or “heteroalkynyl” refer to analkyl, alkenyl, or alkynyl, respectively, in which one or more of thecarbon atoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatoms. Typical heteroatomsinclude, but are not limited to, for example, —O—, —S—, —O—O—, —S—S—,—O—S—, —NR^(a)—, ═N—N═, —N═N—, —N═N—NR′, —PH—, —P(O)₂—, —O—P(O)₂—,—S(O)—, —S(O)₂—, and —SnH₂—, wherein R^(a) is hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, orsubstituted aryl.

The terms “substituted heteroalkyl”, “substituted heteroalkenyl”, or“substituted heteroalkynyl” refer to a heteroalkyl, heteroalkenyl, orheteroalkynyl, respectively, substituted with at least one alkyl,substituted alkyl, or substituent described above in defining the term“substituted alkyl” as an exemplary alkyl substituent.

The term “hydroxyalkyl” refers to an —R^(b)OH, wherein R^(b) is an alkylor substituted alkyl.

The term “amino” refers to —NH₂.

The term “aminoalkyl” refers to an alkyl substituted with an aminohaving having at least one hydrogen replaced with a group chosen fromalkyl, alkenyl, and cycloalkyl. Thus, aminoalkyl refers to the group—R^(c)NR^(d)R^(e), wherein R^(c) is an alkyl and R^(d) and R^(e) areindependently selected from hydrogen, alkyl, alkenyl, and cycloalkyl,provided R^(d) and R^(e) are not both hydrogen.

The term “substituted aminoalkyl” refers to an aminoalkyl wherein atleast one of the alkyl, alkenyl, or cycloalkyl moieties is substitutedwith at least one, preferably 1 to 4, more preferably 1 to 2 groupsselected from those recited herein as appropriate for the recitedmoiety. Thus, for example, a substituted aminoalkyl refers to the group—R^(c)NR^(d)R^(e), wherein R^(c) is an alkyl or substituted alkyl andR^(d) and R^(e) are independently selected from H, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, cycloalkyl, and substitutedcycloalkyl, provided R^(d) and R^(e) are not both hydrogen as in thatcase the group would be amino and not substituted aminoalkyl; and thatat least one of R^(c), R^(d), or R^(e) is a substituted moiety.

The term “alkylamino” refers to an amino having at least one hydrogenreplaced with a group chosen from alkyl, alkenyl, and cycloalkyl. Thus,alkylamino refers to the group —NR^(f)R^(g), wherein R^(f) and R^(g) areindependently selected form H, alkyl, alkenyl, and cycloalkyl, providedat least one of R^(f) or R^(g) is an alkyl.

The term “substituted alkylamino” refers to an alkylamino wherein atleast one of the alkyl, alkenyl, or cycloalkyl moieties is substitutedwith at least one, preferably 1 to 4, more preferably 1 to 2 groupsselected from those recited herein as appropriate substituents for therecited moiety. Thus, for example, a substituted alkylamino refers tothe group —NR^(f)R^(g), wherein R^(f) and R^(g) are independentlyselected form H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,cycloalkyl, and substituted cycloalkyl, provided at least one of R^(f)or R^(g) is an alkyl and at least one of R^(f) or R^(g) is a substitutedmoiety.

The term “disubstituted amino” refers to an amino having both hydrogensreplaced with a group chosen from alkyl, substituted alkyl, alkenyl,substituted alkenyl, cycloalkyl, and substituted cycloalkyl. Thus, forexample, a disubstituted amino refers to the group —NR^(h)R^(i), whereinR^(h) and R^(i) are independently selected from alkyl, substitutedalkyl, alkenyl, substituted alkenyl, cycloalkyl, and substitutedcycloalkyl.

The terms “halogen” and “halo” refer to chlorine, bromine, fluorine, andiodine.

The terms “haloalkyl” or “haloalkoxy” refer to an alkyl or substitutedalkyl; or an alkoxy, respectively, bonded to a single halogen ormultiple halogens. Exemplary haloalkyls containing multiple halogensinclude, but are not limited to, for example, —CHCl₂ and —CF₃. Exemplaryhaloalkoxys containing multiple halogens include, but are not limitedto, for example, trifluoromethoxy (—OCF₃).

The term “alkoxy” refers to an alkyl, substituted alkyl, alkanoyl,substituted alkanoyl, cycloalkyl or substituted cycloalkyl bondedthrough an oxygen linkage (—O-alkyl, —O-substituted alkyl, —O-alkanoyl,—O-substituted alkanoyl, —O-cycloalkyl, or —O-substituted cycloalkyl).Exemplary alkoxy groups include, but are not limited to, for example,methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy,pentoxy, isopentoxy, hexoxy, heptoxy, pentoxy, decanoxy, undecanoxy, anddodecanoxy.

The terms “alkoxyalkyl” or “alkoxyarylthio” refer to an alkyl orsubstituted alkyl; or an arylthio, respectively, bonded to an alkoxy.

The term “alkenyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 12 carbon atoms and at least onecarbon-carbon double bond. Exemplary alkenyls include, but are notlimited to, for example, ethenyl and allyl.

The term “substituted alkenyl” refers to an alkenyl substituted with atleast one substituent, preferably 1 to 4 substituents, more preferably 1to 2 substituents, at any available point of attachment. Exemplarysubstituents include, but are not limited to, for example, alkyl,substituted alkyl, and the substituents described above in defining theterm “substituted alkyl” as exemplary alkyl substituents.

The term “cycloalkenyl” refers to a cyclized alkenyl.

The term “substituted cycloalkenyl” refers to a cyclized substitutedalkenyl.

The term “alkanoyl” refers to an alkyl bonded through a carbonyl(i.e.—C(═O)R^(j), wherein R^(j) is an alkyl).

The term “substituted alkanoyl” refers to an alkanoyl substituted withat least one substituent, preferably 1 to 4 substituents, morepreferably 1 to 2 substituents, at any available point of attachment.Exemplary substituents include, but are not limited to, for example,alkyl, substituted alkyl, and the substituents described above indefining the term “substituted alkyl” as exemplary alkyl substituents.

The terms “alkanoylamino”, “arylcarbonylamino”, “alkylcarbonylamino”, or“arylsulfonylamino” refer to an alkanoyl or substituted alkanoyl; anarylcarbonyl; an alkylcarbonyl; or an arylsulfonyl, respectively, bondedto an amino.

The term “alkanoyloxy” refers to an alkanoyl or substituted alkanoylbonded to an oxygen.

The term “alkynyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 12 carbon atoms and at least onecarbon-carbon triple bond. Exemplary alkynyls include, but are notlimited to, for example, ethynyl; propynyls, such as, for example,prop-1-yn-1-yl and prop-2-yn-1-yl; and butynyls, such as, for example,but-1-yn-1-yl, but-1-yn-3-yl, and but-3-yn-1-yl.

The term “substituted alkynyl” refers to an alkynyl substituted with atleast one substituent, preferably 1 to 4 substituents, more preferably 1to 2 substituents, at any available point of attachment. Exemplarysubstituents include, but are not limited to, for example, alkyl,substituted alkyl, and the substituents described above in defining theterm “substituted alkyl” as exemplary alkyl substituents.

The term “alkylsulfone” refers to —R^(k)S(═O)₂R^(k), wherein R^(k) is analkyl or substituted alkyl.

The term “oxo” refers to the divalent radical ═O.

The term “carbamate” refers to the group —OC(═O)NH₂.

The term “amide” refers to the group —C(═O)NH₂.

The term “sulfonamide” refers to the group —SO₂NH₂.

The terms “substituted amide”, “substituted sulfonamide”, or“substituted carbamate” refer to an amide, sulfonamide, or carbamate,respectively, having at least one hydrogen replaced with a group chosenfrom alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,and substituted cycloalkyl.

A substituted amide, for example, refers to the group —C(═O)NR^(m)R^(n)wherein R^(m) and R^(n) are independently selected from H, alkyl,substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, andsubstituted cycloalkyl, provided at least one of R^(m) or R^(n) is asubstituted moiety.

A substituted sulfonamide, for example, refers to the group—SO₂NR^(o)R^(p) wherein R^(o) and R^(p) are independently selected fromalkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, andsubstituted cycloalkyl, provided at least one of R^(o) or R^(p) is asubstituted moiety.

A substituted carbamate, for example, refers to the group—OC(═O)NR^(q)R^(r) wherein R^(q) and R^(r) are independently selectedfrom alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,and substituted cycloalkyl, provided at least one of R^(q) or R^(r) is asubstituted moiety.

The term “ureido” refers to the group —NHC(═O)NH₂.

The term “cyano” refers to the group —CN.

The terms “cycloalkylalkyl” or “cycloalkylalkoxy” refer to a cycloalkylor substituted cycloalkyl bonded to an alkyl or substituted alkyl; or analkoxy, respectively.

The term “nitro” refers to the group —N(O)₂.

The term “thio” refers to the group —SH.

The term “alkylthio” refers to the group —SR^(s) where R^(s) is analkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl.

The term “thioalkyl” refers to the group —R^(t)S where R^(t) is analkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl.

The term “alkylsulfonyl” refers to the group —S(═O)₂R^(u) where R^(u) isan alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl.

The term “alkylsulfinyl” refers to the group —S(═O)R^(v) where R^(v) isan alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl.

The term “carboxy” refers to the group —C(═O)OH.

The terms “carboxyalkoxy” or “alkoxycarbonylalkoxy” refer to a carboxy,or an alkoxycarbonyl, respectively, bonded to an alkoxy.

The term “alkoxycarbonyl” refers to the group —C(═O)OR^(w) where R^(w)is an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

The term “arylalkoxycarbonyl” refers to an aryl or substituted arylbonded to an alkoxycarbonyl.

The terms “alkylcarbonyloxy” or “arylcarbonyloxy” refer to the group—OC(═O)R^(x), where R^(x) is an alkyl or substituted alkyl, or an arylor substituted aryl, respectively.

The term “carbamoyl” refers to the groups —OC(═O)NH₂, —OC(═O)NHR^(x),and/or —OC(═O)NR^(y)R^(z), wherein R^(y) and R^(z) are independentlyselected from alkyl and substituted alkyl.

The group —NR⁶(C═O)R⁹ refers to a group where R⁶ is selected fromhydrogen, lower alkyl and substituted lower alkyl, and R⁹ is selectedfrom hydrogen, alkyl, substituted alkyl, alkoxy, aminoalkyl, substitutedaminoalkyl, alkylamino, substituted alkylamino, aryl and substitutedaryl.

The term “carbonyl” refers to a C(═O).

The terms “alkylcarbonyl”, “aminocarbonyl”, “alkylaminocarbonyl”“aminoalkylcarbonyl”, or “arylaminocarbonyl” refer to an alkyl orsubstituted alkyl; an amino; an alkylamino or substituted alkylamino; anaminoalkyl or substituted aminoalkyl; or an arylamino, respectively,bonded to a carbonyl.

The terms “aminocarbonylaryl” or “aminocarbonylalkyl” refer to anaminocarbonyl bonded to an aryl or substituted aryl; or an alkyl orsubstituted alkyl, respectively.

The term “sulfonyl” refers to the group S(═O)₂.

The term “sulfinyl” refers to an S(═O).

The term “carboxyalkyl” refers to an alkyl or substituted alkyl bondedto a carboxy.

As used herein, the term “patient” encompasses all mammalian species. Amammalian species includes, but is not limited to, for example, humansand domestic animals, such as, for example, dogs, cats, and horses.

The term “salt(s)”, as employed herein, denotes acidic and/or basicsalts formed with inorganic and/or organic acids and/or bases, and suchterm, as used herein, further includes zwitterion(s) (“inner salts”).

The terms “zwitterion(s)”, as employed herein, denote compound(s)containing both a basic moiety, including but not limited to, forexample, pyridine and imidazole; and an acidic moiety including but notlimited to, for example, a carboxylic acid.

The term “pharmaceutically acceptable”, as employed herein, indicatesthe subject matter being identified as “pharmaceutically acceptable” issuitable and physiologically acceptable for administration to a patient.For example, the term “pharmaceutically acceptable salt(s)” denotessuitable and physiologically acceptable salt(s) for administration to apatient.

The compounds of Formula (I) can also form salt(s). As a result, when acompound of Formula (I) is referred to herein, such reference includes,unless otherwise indicated, salts thereof. In one embodiment, thecompounds of Formula (I) form pharmaceutically acceptable salts. Inanother embodiment, the compounds of Formula (I) form salts that can,for example, be used to isolate and/or purify the compounds of Formula(I). Salt(s) of the Formula (I) compounds can be formed by, for example,reacting a Formula (I) compound with, for example, an equivalent amountof acid or base in a medium that allows the thusly formed salt to, forexample, either precipitate out, or be isolated via lyophilization.

Exemplary acidic salt(s) the compounds of Formula (I) can form withinorganic and/or organic acids include, but are not limited to, forexample, acetates, such as are formed with acetic or trihaloacetic acid;adipates; alginates; ascorbates; aspartates; benzoates;benzenesulfonates; bisulfates; borates; butyrates; citrates;camphorates; camphorsulfonates; cyclopentanepropionates; digluconates;dodecylsulfates; ethanesulfonates; fumarates; glucoheptanoates;glycerophosphates; hemisulfates; heptanoates; hexanoates;hydrochlorides; hydrobromides; hydroiodides; hydroxyethanesulfonates,such as, for example, 2-hydroxyethanesulfonates; lactates; maleates;methanesulfonates; naphthalenesulfonates, such as, for example,2-naphthalenesulfonates; nicotinates; nitrates; oxalates; pectinates;persulfates; phenylpropionates, such as, for example,3-phenylpropionates; phosphates; picrates; pivalates; propionates;salicylates; succinates; sulfates, such as, for example, are formed withsulfuric acid; sulfonates; tartrates; thiocyanates; andtoluenesulfonates, such as, for example, tosylates and undecanoates.Such salts can be formed in accordance with methods known to a person ofordinary skill in the art.

Exemplary basic salt(s) that the compounds of Formula (I) can form withinorganic and/or organic bases include, but are not limited to, forexample, ammonium salts; alkali metal salts, such as, for example,sodium, lithium and potassium salts: alkaline earth metal salts, suchas, for example, calcium and magnesium salts; salts formed with organicbases, such as, for example, benzathines, dicyclohexylamines,hydrabamines (such as, for example,N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glycamides, and t-butyl amines; salts formed with aminoacids, such as, for example, arginine and lysine; and salts formed byusing agents, such as, for example, lower alkyl halides (e.g. methyl,ethyl, propyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), longchain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), and aralkyl halides (e.g. benzyl and phenethylbromides) to quaternize basic nitrogen-containing groups. Such salts canbe formed in accordance with methods known to a person of ordinary skillin the art.

All stereoisomer(s) and geometric isomer(s) of the compounds of Formula(I), either in admixture or in pure or substantially pure form are alsocontemplated herein. Specifically, all enantiomers, tautomers, anddiastereomers of the compounds of Formula (I), as well as mixtures,compounds, racemic compounds, racemic mixtures, and racemates producedtherefrom are contemplated herein. Even more particularly, all opticallyactive isomers of the compounds of Formula (I), including pure orsubstantially pure optically active isomers, i.e., optically activeisomers substantially free of other isomers.

When a compound containing a single enantiomer of a compound of Formula(I) is desired, such compound can be obtained by either resolution ofthe final product or by stereospecific synthesis from eitherisomerically pure starting material(s), or any convenientintermediate(s). Resolution of the final product, an intermediate, or astarting material can be effected by any suitable method known in theart, including, for example, physical methods, such as, for example,fractional crystallization, separation or crystallization ofdiastereomeric derivatives, and separation by chiral columnchromatography. Individual optical isomers can be obtained fromracemates through, for example, conventional methods, such as, forexample, salt formation with an optically active acid followed bycrystallization. The chiral centers of the compounds in accordance withFormula (I) can have the S or R configuration as defined by the IUPAC1974 Recommendations.

Prodrug(s) and/or solvate(s) of the compounds of Formula (I) are furthercontemplated herein.

The term “prodrug(s)”, as employed herein, denotes a compound that, uponadministration to a subject, undergoes chemical conversion via metabolicand/or chemical processes in vivo to yield a compound and/or derivativeof Formula (I), or a salt and/or solvate thereof. Various forms ofprodrug(s) are well known in the art. For examples of such prodrugderivatives, see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et    al. (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and    Application of Prodrugs,” by H. Bundgaard, p. 113-191 (1991); and-   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992).

The term “solvate”, as employed herein, denotes a compound produced bythe chemical interaction of at least one solvent with at least onesolute comprising at least one compound of Formula (I). Exemplarysolvates include, but are not limited to, for example, hydrates.

All numbers expressing quantities of ingredients, properties such asmolecular weight, reaction conditions, and so forth that are preceded bythe word “about” are to be understood as only approximations so thatslight variations above and below the stated number may be used toachieve substantially the same results as the stated number.Accordingly, unless indicated to the contrary, numerical parameterspreceded by the word “about” are approximations that may vary dependingupon the desired properties sought to be obtained by the invention. Atthe very least, and not as an attempt to limit the application of thedoctrine of equivalents to the scope of the claims, each numericalparameter should at least be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques.

It is to be understood that each of the variously stated ranges isintended to be continuous so as to include each numerical parameterbetween the stated minimum and maximum value of each range. It is to befurther understood that, while not intending to limit the applicabilityof the doctrine of equivalents to the scope of the claims, eachnumerical parameter should at least be construed in a manner consistentwith the reported number of significant digits for each numericalparameter and by applying ordinary rounding techniques. It is to be evenfurther understood that, while not intending to limit the applicabilityof the doctrine of equivalents to the scope of the claims, even though anumber may be contained within a numerical range wherein at least one ofthe minimum and maximum numbers of the range is or is not preceded bythe word “about”, each numerical value contained within the range may ormay not be preceded by the word “about”. For Example, a range of about 1to about 10 includes about 1, about 2, 2, about 3, 3, about 4, 4, about5, 5, about 6, 6, about 7, 7, about 8, 8, about 9, 9, and about 10; arange of about 1.1 to about 3.2 includes about 1.1, about 1.2, 1.2,about 1.3, 1.3, about 1.4, 1.4, about 1.5, 1.5, about 1.6, 1.6, about1.7, 1.7, about 1.8, 1.8, about 1.9, 1.9, about 2.0, 2.0, about 2.1,2.1, about 2.2, 2.2, about 2.3, 2.3, about 2.4, 2.4, about 2.5, 2.5,about 2.6, 2.6, about 2.7, 2.7, about 2.8, 2.8, about 2.9, 2.9, about3.0, 3.0, about 3.1, 3.1, and about 3.2; and a range of about 1 to 4includes about 1, 2, about 2, 3, about 3, and 4.

Further, when an amount, concentration, or other value or parameter isgiven as a list of upper values and lower values, such listings areintended to include all ranges formed by pairing any upper value withany lower value, regardless of whether ranges are separately disclosed.

Described herein are compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein Q¹, Q², R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are as defined hereinabove.

In one embodiment, Q² is heteroaryl or substituted heteroaryl.

In another embodiment, Q² is pyrazole, thiazole, or pyrimidine.

In yet another embodiment, R² is hydrogen, alkyl, substituted alkyl,cycloalkyl, or substituted cycloalkyl.

In a further embodiment, Q¹ is aryl or substituted aryl.

In an even further embodiment, Q¹ is phenyl or substituted phenyl.

In a still further embodiment, R³, R⁴, and R⁵ are independently selectedfrom H, alkyl, substituted alkyl, alkoxy, and halogen.

In yet still a further embodiment, R⁷ and R⁸ are independently selectedfrom hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,cycloalkyl, or substituted cycloalkyl.

In still another embodiment, R¹ is NR⁶C(═O)R⁷.

In yet still a further embodiment, R¹ is —NR⁶C(═O)R⁷ and R² is H, alkyl,substituted alkyl, cycloalkyl, or substituted cycloalkyl.

In yet an even further embodiment, Q¹ is phenyl or substituted phenyl;Q² is pyrazole, thiazole, or pyrimidine; R¹ is NR⁶C(═O)R⁷; R² ishydrogen, alkyl, substituted alkyl, cycloalkyl, or substitutedcycloalkyl; R³, R⁴, and R⁵ are independently selected from H, alkyl,substituted alkyl, alkoxy, and halogen; and R⁷ is selected fromhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl,or substituted cycloalkyl.

Still further described herein is at least one pharmaceuticalcomposition comprising at least one compound in accordance with Formula(I), optionally at least one pharmaceutically-acceptable carrier and/ordiluent, and optionally at least one other anti-cancer agent.

Even further described herein is at least one method for treating atleast one proliferative disease comprising administering to a patient inneed thereof an effective amount of at least one compound according toFormula (I), optionally administering either simultaneously orsequentially at least one other anti-cancer agent, and optionallyadministering either simultaneously or sequentially at least one otheranti-cancer treatment.

The phrase “anti-cancer treatment” includes, but is not limited to, forexample, radiation therapy and surgery.

The phrase “other anti-cancer agent” includes any known agent useful fortreating cancer. Examples of other such anti-cancer agent(s) include,but are not limited to, for example, antiangiogenic agents, such as, forexample, linomide, inhibitors of integrin αvβ3 function, angiostatin,and razoxane; antiestrogens, such as, for example, tamoxifen,toremifene, raloxifene, droloxifene, and iodoxifene; progestogens, suchas, for example, megestrol acetate, hydroxyprogesterone, andmedroxyprogesterone; aromatase inhibitors, such as, for example,anastrozole, testolactone, letrozole, borazole, and exemestane;antihormones, such as, for example, aminoglutethimide; syntheticestrogens, such as, for example, chlorotrianisene, diethylstilbestroland 17α-ethinylestradiol; synthetic androgens, such as for example,dromostanolone propionate, fluoxymesterone, and methyltestosterone;antiprogestogens; antiandrogens, such as, for example, flutamide,nilutamide, bicalutamide, and cyproterone acetate; androgens, such as,for example, testosterone; synthetic glucocorticoids, such as, forexample, methylprednisolone, triamcinolone, prednisolone, andprednisone; LHRH agonists and antagonists, such as, for example,gosereline acetate and leuprolide; inhibitors of testosterone5α-dihydroreductase, such as, for example, finasteride;farnesyltransferase inhibitors; anti-invasion agents, such as, forexample, metalloproteinase inhibitors like marimastat and inhibitors ofurokinase plasminogen activator receptor function; VEGF inhibitors, suchas, for example, anti-VEGF antibodies (Avastin) and small molecules,such as, for example, ZD6474, SU6668, Vatalanib, BAY-43-9006, SU11248,CP-547632, and CEP-7055; Her 1 and Her 2 inhibitors including, forexample, anti-Her 2 antibodies (Herceptin); EGFR inhibitors, such as,for example, gefitinib, erlotinib, ABX-EGF, EMD72000, 11F8, andcetuximab; Eg5 inhibitors, such as, for example, SB-715992, SB-743921,and MKI-833; pan Her inhibitors, such as, for example, canertinib,EKB-569, CI-1033, AEE-788, XL-647, mAb 2C4, and GW-572016; Srcinhibitors, such as, for example, Gleevac and Dasatinib; MEK-1inhibitors; MAPK inhibitors; PI3 kinase inhibitors; Met inhibitors;other Aurora kinase inhibitors; PDGF inhibitors, such as, for example,imatinib; IGF1R inhibitors, such as, for example, those disclosed inUnited States Patent Application No. 2004/0044203 A1; other receptor andnon-receptor tyrosine kinase inhibitors; other serine/threonine kinaseinhibitors; CDK inhibitors; antimetabolites, such as, for example,methotrexate, idatrexate, trimetrexate, 5-fluorouracil, tegafur,cytarabine, fludarabine, 6-thioguanine, DON (d-oxo-norleucine or AT-125)and 6-mercaptopurine; intercalating antitumor antibiotics, such as, forexample, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin, mitoxantrone, and mithramycin; platinum derivatives, suchas, for example, cisplatin, oxaliplatin, and carboplatin; alkylatingagents, such as, for example, nitrogen mustard, melphalan, chlorambucil,busulphan, cyclophosphamide, ifosfamide nitrosoureas, dacarbazine,hexamethyl melamine, estramustine, and thiotepa; antimitotic agents,such as, for example, vinblastine, vinflunine, Taxol®(paclitaxel),Taxotere® (docetaxel), 7-O-methylthiomethylpaclitaxel,4-desacetyl-4-methylcarbonatepaclitaxel,3′-tert-butyl-3′-N-tert-butyloxycarbonyl-4-deacetyl-3′-dephenyl-3′-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel,C-4 methyl carbonate paclitaxel, epothilone A, epothilone B, epothiloneC, epothilone D, epothilone analogs, i.e., ixabepilone, and derivativesthereof; inhibitors of integrin signaling; topoisomerase inhibitors,such as, for example, etoposide, teniposide, amsacrine, doxorubicin,daunorubicin, irinotecan, and topotecan; cell cycle inhibitors, such as,for example, flavopyridols; biological response modifiers, such as, forexample, interferon-alpha; monoclonal antibodies, such as for example,rituximab, and gemtuzumab ozogamicin; proteasome inhibitors, such as,for example, Velcade® (bortezomib); SN-8; procarbazine; L-asparaginase;pyridobenzoindole derivatives; ribonucleotide reductase inhibitors; mTORinhibitors; leucovorin; VM-26; interleukins; and hematopoietic growthfactors.

The proliferative disease that can be treated in accordance with theFormula (I) compounds of the invention include, but are not limited to,for example, Aurora kinase associated diseases, such as, for example,cancer, bone diseases, inflammatory diseases, autoimmune diseases,metabolic diseases, viral diseases, fungal diseases, neurological andneurodegenerative disorders, Alzheimer's disease, allergies and asthma,cardiovascular diseases, and hormone related diseases.

In one embodiment, at least one compound of Formula (I) is used to treatcancer.

The cancers Formula (I) compound(s) can be used to treat include, butare not limited to, for example, carcinoma, including, for example, thatof the bladder, breast, colon, kidney, liver, lung (including small celllung cancer), esophagus, gall bladder, ovary, pancreas, stomach, cervix,thyroid, prostate, and skin (including squamous cell carcinoma);hematopoietic tumors of lymphoid lineage, such as, for example,leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia,B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkinslymphoma, hairy cell lymphoma, and Burkett's lymphoma; hematopoietictumors of myeloid lineage, such as, for example, acute and chronicmyelogenous leukemia, myelodysplastic syndrome, and promyelocyticleukemia; tumors of mesenchymal origin, including, for example,fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheralnervous system, including, for example, astrocytoma, neuroblastoma,glioma, and schwannomas; and other tumors, such as, for example,melanoma, seminoma, teratocarcinoma, osteosarcoma, xerodermapigmentosum, keratoacanthoma, thyroid follicular cancer, and Kaposi'ssarcoma.

Yet even further described herein are compounds according to Formula (I)including, but not limited to, for example,N-[4-({4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide;N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-{[3-(methyloxy)phenyl]sulfanyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine;N-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}sulfanyl)phenyl]acetamide;3-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}sulfanyl)-N-methylbenzamide;N-(5-methyl-1H-pyrazol-3-yl)-2-(phenylsulfanyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine;andN-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)sulfanyl)phenyl)benzamide;and pharmaceutically acceptable salts thereof.

Due to the key role protein kinases play in regulating cellularproliferation in general, inhibitors of such kinases may act asreversible cytostatic agents, thereby making such inhibitors useful totreat any disease process featuring abnormal cellular proliferation,e.g., benign prostatic hyperplasia, familial adenomatosis polyposis,neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis,psoriasis, glomerulonephritis, restenosis following angioplasty orvascular surgery, hypertrophic scar formation, inflammatory boweldisease, transplantation rejection, endotoxic shock, and fungalinfections.

Compounds of Formula (I) may modulate apoptosis, and therefore may beuseful in treating cancer, including but not limited to, for example,the cancers already mentioned herein above; treating viral infections,including but not limited to, for example, herpes virus, pox virus,Epstein-Barr virus, Sindbis virus, and adenovirus; preventing AIDS fromdeveloping in HIV-infected individuals; treating autoimmune diseases,including but not limited to, for example, systemic lupus,erythematosus, autoimmune mediated glomerulonephritis, rheumatoidarthritis, psoriasis, inflammatory bowel disease, and autoimmunediabetes mellitus; treating neurodegenerative disorders, including butnot limited to, for example, Alzheimer's disease, AIDS-related dementia,Parkinson's disease, amyotrophic lateral sclerosis, retinitispigmentosa, spinal muscular atrophy, and cerebellar degeneration;treating myelodysplastic syndromes; treating aplastic anemia; treatingischemic injury associated with myocardial infarctions, strokes, andreperfusion injury; treating arrhythmias; treating artherosclerosis;treating toxin-induced or alcohol related liver diseases; treatinghematological diseases, including but not limited to, for example,chronic anemia and aplastic anemia; treating degenerative diseases ofthe musculoskeletal system, including but not limited to, for example,osteoporosis and arthritis; treating aspirin-sensitive rhinosinusitis;treating cystic fibrosis; treating multiple sclerosis; treating kidneydiseases; and treating cancer pain.

Compounds of Formula (I) may also modulate the level of cellular RNA andDNA synthesis, and as a result could be useful in treating viralinfections, including but not limited to, for example, HIV; humanpapilloma virus; herpes virus; pox virus; Epstein-Barr virus; Sindbisvirus; and adenovirus.

Compounds of Formula (I) may also be useful in the chemoprevention ofcancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by blocking the initiating mutagenic event, by blockingprogression of pre-malignant cells that have already suffered an insult,or by inhibiting tumor relapse.

Compounds of Formula (I) may also be useful in inhibiting tumorangiogenesis and metastasis.

The compounds of Formula (I) may further be employed adjuvant tosurgery. For example, at least one compound in accordance with Formula(I) may be used in combination with antibody therapy, or in concert withvaccine/immune modulating agents used to treat cancer.

In one embodiment, the patient is an animal.

In another embodiment, the patient is a human.

The compounds of Formula (I) can be administered by any means suitablefor the condition to be treated, which can depend on the need forsite-specific treatment or quantity of drug to be delivered.

A pharmaceutical composition comprising at least one compound accordingto Formula (I) can, for example, be delivered orally via any acceptableand suitable oral form, including but not limited to, for example,tablets; troches; lozenges; aqueous or oily suspensions; dispersiblepowders or granules; emulsions; hard or soft capsules; syrups; andelixirs. Pharmaceutical compositions intended for oral use can beprepared according to any method known in the art for manufacturingpharmaceutical compositions. In order to provide pharmaceuticallyelegant and palatable preparations, a pharmaceutical composition inaccordance with the invention can contain at least one agent selectedfrom sweetening agents, flavoring agents, coloring agents, andpreserving agents.

A tablet can be prepared by, for example, admixing at least one compoundaccording to Formula (I) with at least one non-toxic pharmaceuticallyacceptable excipient suitable for the manufacture of tablets, includingbut not limited to, for example, inert diluents, such as, for example,calcium carbonate, sodium carbonate, lactose, calcium phosphate, andsodium phosphate; granulating and disintegrating agents, such as, forexample, microcrystalline cellulose, sodium crosscarmellose, cornstarch, and alginic acid; binding agents, such as, for example, starch,gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating agents, suchas, for example, magnesium stearate, stearic acid, and talc.Additionally, a tablet can either be uncoated, or coated by knowntechniques to either mask the bad taste of an unpleasant tasting drug,or delay disintegration and absorption of the active ingredient in thegastrointestinal tract thereby sustaining the effects of the activeingredient for a longer period. For example, water soluble taste maskingmaterials, including but not limited to, for example,hydroxypropyl-methylcellulose and hydroxypropyl-cellulose, or time delaymaterials, including but not limited to, for example, ethyl celluloseand cellulose acetate buryrate can be used.

Hard gelatin capsules can be prepared by, for example, mixing at leastone compound according to Formula (I) with at least one inert soliddiluent, including but not limited to, for example, calcium carbonate;calcium phosphate; and kaolin. Soft gelatin capsules can be prepared bymixing at least one compound according to Formula (I) with at least onewater soluble carrier, including but not limited to, for example,polyethylene glycol; and oil mediums, such as, for example, peanut oil,liquid paraffin, and olive oil.

An aqueous suspension can be prepared by admixing at least one compoundaccording to formula (I) with at least one excipient suitable for themanufacture of an aqueous suspension, including but not limited to, forexample, suspending agents, such as, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth, and gum acacia;dispersing or wetting agents, such as, for example, anaturally-occurring phosphatide, such as, for example, lecithin;condensation products of alkylene oxide with fatty acids, such as, forexample, polyoxyethylene stearate; condensation products of ethyleneoxide with long chain aliphatic alcohols, such as, for exampleheptadecaethylene-oxycetanol; condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol, such as, forexample, polyoxyethylene sorbitol monooleate; and condensation productsof ethylene oxide with partial esters derived from fatty acids andhexitol anhydrides, such as, for example, polyethylene sorbitanmonooleate. An aqueous suspension can also contain at least onepreservative, such as, for example, ethyl and n-propylp-hydroxybenzoate; at least one coloring agent; at least one flavoringagent; and/or at least one sweetening agent, including but not limitedto, for example, sucrose, saccharin, and aspartame.

Oily suspensions can be prepared, for example, by suspending at leastone compound according to Formula (I) in either a vegetable oil, suchas, for example, arachis oil; olive oil; sesame oil; and coconut oil, orin mineral oil, such as, for example, liquid paraffin. An oilysuspension can also contain a thickening agent, such as, for example,beeswax; hard paraffin; and cetyl alcohol. In order to provide apalatable oily suspension, at least one of the sweetening agents alreadydescribed hereinabove, and/or at least one flavoring agent can be addedto the oily suspension. An oily suspension can further contain apreservative, including but not limited to, for example, ananti-oxidant, such as, for example, butylated hydroxyanisol, andalpha-tocopherol.

Dispersible powders and granules can be prepared by admixing at leastone compound according to Formula (I) with at least one dispersingand/or wetting agent; at least one suspending agent; and/or at least onepreservative. Suitable dispersing agents, wetting agents, and suspendingagents are as already described above. In addition, dispersible powdersand granules can also contain excipients, including but not limited to,for example, sweetening agents; flavoring agents; and coloring agents,and/or preservatives including but not limited to, for example,anti-oxidants, such as, for example, ascorbic acid.

An emulsion of at least one compound according to Formula (I) can beprepared as an oil-in-water emulsion. The oil phase can be provided bybut is not limited to, for example, a vegetable oil, such as, forexample, olive oil and arachis oil; a mineral oil, such as, for example,liquid paraffin; and mixtures thereof. Suitable emulsifying agentsinclude but are not limited to, for example, naturally-occurringphosphatides, such as, for example, soy bean lecithin; esters or partialesters derived from fatty acids and hexitol anhydrides, such as, forexample, sorbitan monooleate; and condensation products of partialesters with ethylene oxide, such as, for example, polyoxyethylenesorbitan monooleate. An emulsion can also contain a sweetening agent, aflavoring agent, a preservative, and/or an antioxidant.

Syrups and elixirs can contain a sweetening agent, including but notlimited to, for example, glycerol; propylene glycol; sorbitol; andsucrose. Syrups and elixirs can also contain a demulcent, apreservative, a flavoring agent, a coloring agent, and/or anantioxidant.

A pharmaceutical composition comprising at least one compound accordingto Formula (I) can, for example, also be delivered intravenously,subcutaneously, and/or intramuscularly via any acceptable and suitableinjectable form, including but not limited to, for example, sterileaqueous solutions comprising acceptable vehicles and solvents, such as,for example, water, Ringer's solution, and isotonic sodium chloridesolution; sterile oil-in-water microemulsions; and aqueous or oleagenoussuspensions.

A sterile injectable oil-in-water microemulsion can be prepared by 1)dissolving at least one compound according to Formula (I) in an oilyphase, such as, for example, a mixture of soybean oil and lecithin;combining the compound containing oil phase with a water and glycerolmixture; and 3) processing the combination to form a microemulsion.

A compound according to Formula (I) can be introduced into a patient'sblood-stream by administering the Formula (I) compound containinginjectable solution and/or microemulsion as, for example, a local bolusinjection. If maintaining a constant circulating concentration of theFormula (I) compound is desired, a continuous intravenous deliverydevice, such as, for example, a Deltec CADD-PLUS™ model 5400 intravenouspump, can be utilized.

A sterile aqueous or oleaginous suspension can be prepared in accordancewith methods already known in the art. For example, a sterile aqueoussolution or suspension can be prepared with a non-toxicparenterally-acceptable diluent or solvent, such as, for example,1,3-butane diol; and a sterile oleaginous suspension can be preparedwith a sterile non-toxic acceptable solvent or suspending medium, suchas, for example, sterile fixed oils including but not limited to, forexample, synthetic mono- or diglycerides; and fatty acids including butnot limited to, for example, oleic acid.

A pharmaceutical composition comprising at least one compound accordingto Formula (I) can, for example, further be administered via anyacceptable and suitable rectal form, including but not limited to, forexample, a suppository. A suppository can be prepared by mixing at leastone Formula (I) compound with a suitable non-irritating excipient thatis liquid at rectal temperatures but solid at least one temperaturebelow rectal temperature. Exemplary non-irritating excipients includebut are not limited to, for example, cocoa butter; glycerinated gelatin;hydrogenated vegetable oils; mixtures of polyethylene glycols of variousmolecular weights; and fatty acid esters of polyethylene glycol.

A compound in accordance with Formula (I) can further be administeredvia any acceptable and suitable topical route including but not limitedto, for example, creams; ointments; jellies; solutions; suspensions,transdermal patches; intranasal inhalers, etc. For purposes of thisapplication, topical application shall include mouth washes and gargles.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions that may contain, for example, benzyl alcohol or othersuitable preservatives, absorption promoters to enhance absorptionand/or bioavailability, and/or other solubilizing or dispersing agentssuch as those known in the art.

An “effective amount” of a compound in accordance with the Formula (I)can be determined by one of ordinary skill in the art, and includesexemplary dosage amounts for a mammal of from about 0.05 to 100 mg/kg ofbody weight of active compound per day, which may be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day.

The specific dose level and frequency of dosage for any particularsubject, however, may be varied and generally depends on a variety offactors, including, but not limited to, for example, the bioavailabilityof the specific Formula (I) compound(s) in the administered form;metabolic stability and length of action of the specific Formula (I)compound(s); species, age, body weight, general health, sex, and diet ofthe subject; mode and time of administration; rate of excretion; drugcombination; and severity of the particular condition.

If formulated as a fixed dose, a combination product can, for example,utilize a dosage of the compound of Formula (I) within the dosage rangedescribed above and the dosage of another anti-cancer agent/treatmentwithin the approved dosage range for such known anti-canceragent/treatment. If a combination product is inappropriate, the compoundof Formula (I) and the other anti-cancer agent/treatment can, forexample, be administered simultaneously or sequentially. If administeredsequentially, the invention is not limited to any particular sequence ofadministration. For example, compounds of Formula (I) can beadministered either prior to, or after, administration of the knownanti-cancer agent or treatment.

The compounds of Formula (I) can also be formulated or co-administeredwith other therapeutic agents that are selected for their particularusefulness in administering therapies associated with the aforementionedconditions. For example, the compounds of the invention may beformulated with agents to prevent nausea, hypersensitivity, and/orgastric irritation, such as, for example, antiemetics and H₁ and H₂antihistaminics.

The above other therapeutic agents, when employed in combination withthe compounds of Formula (I), can be used, for example, in those amountsindicated in the Physicians' Desk Reference (PDR) or as otherwisedetermined by one of ordinary skill in the art.

In general, the compounds of Formula (I) can be prepared in accordancewith Scheme I and the general knowledge of one skilled in the art.Tautomers and solvates (e.g., hydrates) of the compounds of Formula (I)are also within the scope of the invention. Methods of solvation aregenerally known in the art. Accordingly, the compounds of the inventioncan be in the free or hydrate form, and can be obtained by methodsexemplified in Scheme I. The abbreviations utilized in Steps 1-4 ofScheme I are as defined in the Examples set forth hereinbelow.

Step 1: Compound II can be prepared by heating a mixture of theappropriately substituted 1-amino-1H-pyrrole-2-carboxamide with areagent, such as, for example, ethyl chloroformate and an appropriatebase, such as, for example, pyridine in a solvent, such as, for example,dioxane. The resulting pyrrolotriazine-2,4-dione II can then be heatedwith a chlorinating agent, such as, for example, phosphorus oxychloridein the presence of a base, such as for example, diisopropylethylamine togive compound III.

Step 2: Compound V is produced by coupling compound III with anappropriately substituted aniline IV. The coupling can be carried out inthe presence of a base, such as, for example, disopropylethylamine in asolvent, such as, for example, isopropyl alcohol.

Step 3: A compound in accordance with Formula (I) is obtained bytreating compound V with an appropriately functionalized arylthiol VIand a base, such as, for example, potassium carbonate at elevatedtemperatures.

It is of import to note that other compounds of Formula (I) can bereadily prepared using methods generally known to a person of ordinaryskill in the art including but not limited to, for example, the variousmethods of preparation utilized in the Examples set forth hereinbelow.

Assays

At least one compound of Formula (I), including the compounds describedin the examples hereof, has been tested in at least one assay describedbelow and shown activity as an inhibitor of at least one of Aurorakinase A, B, and/or C.

Cell-Based Assay for Histone H3 Phosphorylation

To determine the ability of compounds to inhibit the function of theAurora kinases in human cells, the phosphorylation status of Histone H3(HH3) on Serine 10 was analyzed. HH3 is a chromatin proteinphosphorylated on at least 2 serine residues including Ser-10 andSer-28. Ser-10 on centromeric HH3 is phosphorylated in the G2 phase ofthe cell cycle and by mitosis. Ser-10 is phosphorylated over the entirechromosome. Phosphorylation at this site on HH3 regulates the initiationof chromatin condensation and appears to require the Aurora kinases.

Using this knowledge, an in-cell western assay was developed to measurethe extent of HH3 phosphorylation by Aurora kinases in cells arrested inmitosis. Specifically, HCT-116 colorectal cancer cells were plated in a96 well plate and allowed to grow for 6 hours. After 6 hours, Nocodazolewas added to the wells at a final concentration of 15 ug/mL, and thecells were incubated for an additional 16 hours. The Nocodazoletreatment caused the cells to arrest in mitosis with maximal HH3phosphorylation. At the end of the 16 hour Nocodazole treatment, thecells were treated with various concentrations of compounds within thescope of Formula (I) for about 2 hours to determine the ability of suchFormula (I) compounds to reverse Aurora Kinase dependent HH3phosphorylation. At the end of the experiment, Formula (I) compound andcontrol treated cells were fixed in 4% formaldehyde, and then stainedwith a rabbit polyclonal antibody specific for the epitope containingphosphorylated Ser-10 (Upstate #06-570). At the same time, cells werealso stained using a mouse monoclonal to a housekeeping protein(anti-actin, Chemicon 1501R) to control for cell number in each well.Primary antibodies were detected using Alexa dye labeled secondaryantibodies (anti-mouse-800 (Rockland #610-131-121), and anti-rabbit-680(Molecular Probes#A21076)). The assay plates were subsequently analyzedfor fluorescence in both channels (800 and 680) using a Licor Odysseyinstrument. Fluorescence specific to phospho-HH3 was normalized tofluorescence specific to actin. Percent inhibition of HH3phosphorylation relative to vehicle treated cells was determined foreach concentration of Formula (I) compound tested. The concentrationrequired to give 50% inhibition of HH3 phosphorylation (P—HH3 IC50s) wasalso determined for each Formula (I) compound tested.

Phenotypic Analysis of Cells Treated with Aurora Kinase Inhibitors

The role of the Aurora kinases in regulating proper cell division hasbeen extensively studied. Genetic disruption of these kinases in modelorganisms and mammalian cells has demonstrated specific phenotypesassociated with loss of Aurora kinase function. Specifically, mitoticdefects including the appearance of polyploid cells resulting fromfailure at cytokinesis is a marked and measurable phenotype in cellslacking Aurora kinase activity. Furthermore, these polyploid cellsundergo apoptosis upon subsequent attempts at cell division. Based onthese well characterized phenotypes, a functional assay was developed tosimultaneously measure polyploidy and apoptosis in cells treated withAurora kinase inhibitors.

DNA content can be readily quantified by adding propidium iodide (PI) tofixed cells. Propidium iodide binds cellular DNA and fluoresces whenilluminated. Fluorescence is directly proportional to cellular DNAcontent. As a result, one can determine the percentage of cells in apopulation at each phase of the cell cycle and also the percentage ofcells with greater than 4N DNA content (polyploid cells) by using flowcytometry.

Numerous techniques are available to detect apoptosis in mammaliancells. One event that occurs in most cell types once the cell hascommitted to apoptotic cell death is the specific proteolytic cleavageof the nuclear protein Poly-ADP Ribose Polymerase (PARP). This cleavageis carried out by the apoptosis effector caspases, CASP-3 and CASP-7.Commercial antibodies are available that detect the 85 kDa fragment ofcleaved PARP (PARP-p85) present in apoptotic cells but not full lengthPARP present in living cells. These antibodies are useful fordetermining the fraction of apoptotic cells in a population at a giventime.

By combining PI staining for DNA content and staining for PARP-p85, anassay was developed to track the induction of both polyploidy andapoptosis in cells treated with various concentrations of variousFormula (I) compounds. The treated cells were analyzed in accordancewith such assay at a variety of times following treatment. By using thisassay, the Formula (I) compounds that induced polyploidy after 24 hoursof treatment and apoptosis at 48 hours after treatment could beidentified, and was consistent with specific inhibition of the Aurorakinases.

Cell Cytotoxicity Assays

To determine the long term effects on cells treated with compoundsaccording to Formula (I), a cytotoxicity assay was used to measureoverall cellular viability following 72 hours of Formula (I) compoundexposure. The cytotoxicity assay uses soluble tetrazolium salt, MTS,(Promega Corporation; Madison, Wis.) which is metabolically converted toa colored product in living cells but not dead cells.

Cells were seeded in 96 well culture plates. After 24 hours, the Formula(I) compound was added and serial diluted. After 72 hours of exposure,the percent inhibition of MTS conversion relative to vehicle treatedcells was determined for each concentration of Formula (I) compoundtested. The concentration required to give 50% inhibition of MTSconversion (MTS IC50s) was also determined for each Formula (I) compoundtested.

The cytotoxicity assay was performed on at least 12 human cancer celllines including breast (BT-549, DU4475, MDA-MB-468, MDA-MB-231),prostate (PC-3, DU145, LNCaP), lung (NCI-H446, SHP-77), ovary (A2780),colon (HCT116), and hematologic (CCRF-CEM). This panel of cell linesenabled relative sensitivities of the various lines to cell killing byeach Formula (I) compound tested to be determined.

IC₅₀ Values

At least one compound of Formula (I) showed activity in at least one ofthe above referenced assays via an IC₅₀ value of between about 0.01 toabout 100 μM. In one embodiment, at least one compound of Formula (I)showed activity in at least one of the above referenced assays via anIC₅₀ value of less than about 1.0 μM. In another embodiment, at leastone compound of Formula (I) showed activity in at least one of the abovereferenced assays via an IC₅₀ value of less than about 0.5 μM.

EXAMPLES

The invention is further defined in the following Examples. It should beunderstood that the Examples are given by way of illustration only. Fromthe above discussion and the Examples, one skilled in the art canascertain the essential characteristics of the invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications to adapt the invention to various uses and conditions.As a result, the invention is not limited by the illustrative examplesset forth hereinbelow, but rather defined by the claims appended hereto.

All temperatures are in degrees Celsius (° C.) unless indicatedotherwise herein.

All reactions were carried out with continuous magnetic stirring underan atmosphere of dry nitrogen or argon. All evaporations andconcentrations were carried out on a rotary evaporator under reducedpressure. Commercial reagents were used as received without additionalpurification. Solvents were commercial anhydrous grades and were usedwithout further drying or purification. Flash chromatography wasperformed using silica gel (EMerck Kieselgel 60, 0.040-0.060 mm).

The following abbreviations are employed herein: n-BuOH: n-butylalcohol, CDCl₃: chloroform-²H (1), D₂O: deuterium oxide, DCM:N-(3,4-dichlorophenyl)-2-methyl-acrylamide, DMA: dimethylamine, DMF:dimethyl formamide, DMSO: dimethyl sulfoxide, EDC: 1,2-dichloroethane,EtOH: ethanol, EtOAc: ethyl acetate, HCl: hydrochloric acid, HOAc:acetic acid, IPA: isopropyl alcohol, K₂CO₃: potassium carbonate, MeOH:methanol, MgSO₄: magnesium sulfate, NaHCO₃: sodium bicarbonate, Na₂SO₄:sodium sulfate, NH₄Cl: ammonium chloride, NH₃: ammonia, N₂: nitrogen,POCl₃: phosphorous oxychloride, THF: tetrahydrofuran, TFA:trifluoroacetic acid, Bn: benzyl, Me: methyl, Et: ethyl, min.:minute(s), h or hr(s): hour(s), L: liter, mL: milliliter, μL:microliter, g: gram(s), mg: milligram(s), mol.: moles, mmol:millimole(s), meq.: milliequivalent, RT or rt: room temperature, ret.t.: HPLC retention time (minutes), sat or sat'd: saturated, aq.:aqueous, TLC: thin layer chromatography, HPLC: high performance liquidchromatography, RP HPLC: reverse phase HPLC, Prep HPLC: preparativereverse phase HPLC, LC/MS: high performance liquid chromatography/massspectrometry, MS: mass spectrometry, NMR: nuclear magnetic resonance,and mp: melting point.

HPLC Conditions:

In Examples 1-4 the Analytical Reverse Phase HPLC ret. t. was obtainedwith the column type and length, flow rate, and linear gradient elutionidentified in each example. Unless indicated otherwise herein, allgradients started with 100% solvent A (MeOH:water:TFA=1:9:0.01) and 0%solvent B, and ended with 100% solvent B (MeOH:water:TFA=1:9:0.01) and0% solvent A. UV detection was conducted at 220 nm.

Prep. HPLC was performed with a linear gradient elution using H₂O/MeOHmixtures buffered with 0.1% trifluoroacetic acid and detection at 220 nmon one of the following columns: Shimadzu S5 ODS-VP 20×100 mm (flowrate=9 mL/min), or YMC S10 ODS 50×500 mm (flow rate=50 mL/min), or YMCS10 ODS 30×500 mm (flow rate=20 mL/min).

All final products were characterized by ¹H NMR, RP HPLC, electrosprayionization (ESI MS) or atmospheric pressure ionization (API MS) massspectrometry. ¹H NMR spectra were obtained on either a 500 MHz JEOL or a400 MHz Bruker instrument. Field strengths are expressed in units of □(parts per million, ppm) relative to the solvent peaks, and peakmultiplicities are designated as follows: s, singlet; d, doublet; dd,doublet of doublets; dm, doublet of multiplets; t, triplet; q, quartet;br s, broad singlet; m, multiplet.

Example 1N-[4-({4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide

1A. Pyrrolo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione

Ethyl chloroformate (4.9 ml, 51 mmol) was added dropwise to a stirredmixture of 1-amino-1H-pyrrole-2-carboxamide (5.85 gm, 46.7 mmol, Journalof Heterocyclic Chemistry, 1994, 31, 781) and dry pyridine (4.2 mL, 51mmol) in dry dioxane (48 mL) under N₂ at RT. The mixture was heated atreflux for 1 hr and then the solvent was removed. The residue was heatedat 155° C. for 17 hr and then allowed to cool to RT. The cooled residuewas triturated with MeOH. The solid precipitate was collected byfiltration and washed with cold MeOH to give 4.43 g 1A (63% yield). ¹HNMR (DMSO-d₆): 6.34 (br. s, 1H), 6.75 (br. s, 1H), 7.12 (br.s, 1H); MS:152 (M+H)⁺; and RP HPLC ret. t.: 0.36 min (YMC Xterra S 7: 3.0×50 mmcolumn, 2 min gradient, 5 mL/min.

1B. 2,4-Dichloropyrrolo[1,2-f][1,2,4]triazine

A mixture of 1A (4.7 gm, 31.1 mmol), POCl₃ (8.81 mL, 3 equiv), anddiisopropylethylamine (10.8 mL, 2 equiv) in toluene was heated in apressure vessel at 125° C. for 24 hr. After cooling to RT, the mixturewas poured into an ice-cooled sat. aq. solution of NaHCO₃ with stirring.After 10 min, the aq. phase was separated and washed with DCM (3×200mL). The combined organic phases were washed with brine, dried (Na₂SO₄),and the solvent removed. Silica gel column chromatography (elution withDCM) gave 4.25 g 1B (81% yield) as a yellow solid. ¹H NMR (CDCl₃): 6.96(m, 1H), 7.03 (m, 1H), 7.85 (m, 1H); MS: 187.9 (M+H)⁺; and RP HPLC ret.t.: 1.63 min. (YMC Xterra S 5: 4.6×50 mm column, 2 min gradient, 5mL/min).

1C.2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine

A mixture of 1B (1.50 gm, 8 mmol), 5-methyl-1H-pyrazol-3-amine (801 mg,1 equiv), and diisopropylethylamine (2.37 mL, 1.7 equiv) in IPA (8 mL)was stirred at RT overnight. MeOH (2 mL) was added and 1.7 g 1C (86%yield) was collected by filtration. ¹H NMR (MeOH-d₄): 2.35 (s, 3H), 6.58(br. s, 1H), 6.71 (br.s, 1H), 7.02 (br. s, 1H), 7.59 (br.s, 1H); MS: 249(M+H)⁺; and RP HPLC ret. t.: 1.44 min (Phenomenex-Luna S 10: 3.0×50 mmcolumn, 2 min gradient, 4 mL/min).

1D.2-(4-Aminophenylthio)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine

A mixture of 1C (300 mg, 1.21 mmol), 4-aminobenzenethiol (606 mg, 4equiv) and K₂CO₃ (342 mg, 2 equiv) in dry DMF under a N₂ atmosphere washeated at 120° C. After 1 hr, the mixture was cooled to RT, diluted with7 mL water, and left stirring for 1 hr. The precipitate was collected byfiltration, washed with water and dried. Silica gel columnchromatography (step gradient elution with mixtures of DCM containing 0,2.5, 5, 7.5, 10, 20% MeOH) gave 422 mg 1D as a white solid. ¹H NMR(MeOH-d₄): 2.25 (s, 3H), 5.87 (s, 1H), 6.62 (m, 1H), 6.77 (m, 2H), 6.93(m, 1H), 7.36 (m, 2H), 7.47 (s, 1H); MS: 338 (M+H)⁺; and RP HPLC ret.t.: 2.04 min (Phenomenex-Luna S 10: 4.6×50 mm column, 3 min gradient, 4mL/min).

1E.N-[4-({4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide

A solution of cyclopropanecarbonyl chloride (9.1 uL, 0.1 mmol) in dryDCM (0.8 mL) was added to a solution of 1D (33.7 mg, 0.1 mmol) in drypyridine (0.8 mL) in a vial. The vial was sealed and left stirring overthe weekend. Prep. HPLC was used to isolate 13 mg 1E (27% yield) as theTFA salt. ¹H NMR (MeOH-d₄): 0.84 (m, 2H), 0.91 (m, 2H), 1.72 (m, 1H),2.12 (s, 3H), 5.80 (m, 1H), 6.63 (m, 1H), 7.02 (m, 1H), 7.56 (m, 1H),7.58 (m, 4H); MS: 406 (M+H)⁺; and RP HPLC ret. t.: 3.23 min(Phenomenex-Luna S10: 4.6×50 mm column, 4 min gradient, 4 mL/min).

Example 2N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-{[3-(methyloxy)phenyl]sulfanyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine

2A.2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine

A mixture of 1B (977 mg, 5.2 mmol), 5-cyclopropyl-1H-pyrazol-3-amine(640 mg, 1 equiv), and diisopropylethylamine (1.54 mL, 1.7 equiv) in 5mL IPA was stirred at RT overnight. The precipitate was collected byfiltration to give 1.18 g 2A (83% yield). ¹H NMR (CDCl₃): 0.67 (m, 2H),0.86 (m, 2H), 1.77 (m, 1H), 6.6 (br. s, 1H), 6.54 (br.s, 1H), 6.79 (br.s, 1H), 7.42 (br.s, 1H); MS: 275 (M+H)⁺; and RP HPLC ret. t.: 1.56 min(Phenomenex-Luna S10: 3.0×50 mm column, 2 min gradient, 4 mL/min).

2B.N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-{[3-(methyloxy)phenyl]sulfanyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine

A mixture of 2A (28 mg, 0.1 mmol), 3-methoxybenzenethiol (61 uL, 5equiv) and K₂CO₃ (28 mg, 2 equiv) in dry DMF (0.1 mL) under an N₂atmosphere was heated at 120° C. After 6 hr, the mixture was cooled toRT and applied to a Phenomenex strata-X-C cationic cartridge. Thecartridge was subsequently washed with MeOH and a crude product waseluted with a 2 N solution of NH₃ in MeOH. The crude product waspurified by prep. HPLC to produce 17 mg 2B (44% yield). ¹H NMR(MeOH-d₄): 0.61 (m, 2H), 0.92 (m, 2H), 1.80 (m, 1H), 3.81 (s, 3H), 5.8(br.s, 1H), 6.63 (m, 1H), 6.94 (m, 1H), 7.01 (br.s, 1H), 7.21 (br.s,1H), 7.37 (br.s, 1H), 7.49 (s, 1H), 7.75 (s, 1H); MS: 379 (M+H)⁺; and RPHPLC ret. t.: 1.88 min (Phenomenex-Luna S10: 4.6×50 mm column, 3 mingradient, 4 mL/min).

Example 3N-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f]1,2,4]triazin-2-yl}sulfanyl)phenyl]acetamide

A mixture of 2A (55 mg, 0.2 mmol), N-(4-mercaptophenyl)acetamide (167mg, 5 equiv) and K₂CO₃ (55 mg, 2 equiv) in dry DMF (0.1 mL) under an N₂atmosphere was heated at 120° C. After 3 hr, the mixture was cooled toRT, diluted with MeOH, and filtered. Prep. HPLC was used to isolate 53mg title product (66% yield). ¹H NMR (MeOH-d₄): 0.60 (m, 2H), 0.92 (m,2H), 1.79 (m, 1H), 2.16 (s, 3H), 5.8 (br.s, 1H), 6.61 (br., 1H), 6.93(m, 1H), 7.47 (br.s, 1H), 7.57 (m, 2H), 7.71 (m, 2H); MS: 406 (M+H)⁺;and RP HPLC ret. t.: 1.68 min (Phenomenex-Luna S10: 4.6×50 mm column, 3min gradient, 4 mL/min).

Example 43-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}sulfanyl)-N-methylbenzamide

4A.3-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-ylthio)benzoicacid

A mixture of 2A (99 mg, 0.36 mmol) and 3-mercaptobenzoic acid (278 mg, 5equiv) in 1.0 mL n-BuOH was heated in a Smith Synthesizer microwavereactor (Personal Chemistry, Sweden) at 170° C. for 15 hr. After coolingto RT, the mixture was diluted with MeOH, and the precipitate wascollected by filtration to give 95 mg 4A (67% yield). ¹H NMR (DMSO-d₆with a drop of D₂O): 0.49 (m, 2H), 0.86 (m, 2H), 1.70 (m, 1H), 5.61 (s,1H), 6.61 (m, 1H), 7.25 (m, 1H), 7.60 (m, 2H), 7.85 (m, 1H), 8.03 (m,1H), 8.11 (s, 1H); MS: 393 (M+H)⁺; and RP HPLC ret. t.: 1.76 min(Phenomenex-Luna S10: 4.6×50 mm column, 3 min gradient, 4 mL/min).

4B.3-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}sulfanyl)-N-methylbenzamide

Methylamine (0.28 mL, 1.4 equiv, 2.0 M solution in THF) followed by EDC(58 mg, 1.5 equiv) were added to a suspension of 4A (78 mg, 0.2 mmol) indry DCM (0.5 mL) at RT under an N₂ atmosphere. After stirring overnight,prep. HPLC was used to isolate 34 mg 4B (43% yield). ¹H NMR (MeOH-d₄):0.57 (m, 2H), 0.92 (m, 2H), 1.77 (m, 1H), 2.92 (s, 3H), 5.74 (br.s, 1H),6.62 (br., 1H), 6.94 (br.s, 1H), 7.48 (br.s, 1H), 7.56 (m, 1H), 7.79 (m,1H), 7.95 (m, 1H), 8.12 (s, 1H); MS: 406 (M+H)⁺; and RP HPLC ret. t.:1.63 min (Phenomenex-Luna S10: 4.6×50 mm column, 3 min gradient, 4mL/min).

Example 5N-(5-methyl-1H-pyrazol-3-yl)-2-(phenylsulfanyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

Benzothiophenol (0.1 mL, 2 equiv) was added to suspension of K₂CO₃ (151mg, 2.3 eq.) in 1 mL DMF at rt. After 10 min, 1C (120 mg, 1 eq.) wasadded as a 3 mL DMF solution. The reaction was stirred at 110° C.overnight, resulting in product formation as shown by LCMS. The reactionwas then extracted using ethyl acetate and the combined organic phaseswashed with water and brine. The organic layer was dried with MgSO₄ thenconcentrated. The crude mixture was triturated with ethyl acetate toobtain the final product. MS: 323 [M+H]⁺; ¹H NMR (DMSO-d₆): 12.08 (s,1H), 10.63 (s, 1H), 7.65 (m, 3H); 7.57 (d, 1H), 7.49 (d, 2H), 7.23 (s,1H), 6.59 (t, 1H), 5.61 (s, 1H), 2.27 (s, 3H).

Example 6N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)sulfanyl)phenyl)benzamide

6A. N-(4-Mercapto-phenyl)-benzamide

Benzoyl chloride (5.14 mL, 44.28 mL) was added dropwise to a mixture of4-aminophenol disulfide (5.0 g, 20.13 mmol) and TEA (7.01 mL, 50.3 mmol)in 60 mL DCM at 0° C. The reaction was allowed to stir overnight. Theresulting precipitate was collected by filtration. The solid was washedwith MeOH and water and then dried. The solid was combined with 200 mLof concentrated HOAc, and 5.0 equiv of zinc powder was added. Thereaction was monitored by LCMS. When the reaction was complete, theacetic acid solution was concentrated to approximately 20 mL in volume.The crude mixture was then extracted with water and EtOAc. The organiclayer was dried with MgSO₄ then concentrated. MS: 228 [M+H]⁺; ¹H NMR(DMSO-d₆): 10.23 (s, 1H), 7.94 (d, 2H), 7.81 (d, 2H), 7.56 (m, 3H), 7.28(d, 2H), 5.31 (s, 1H).

6B.N-{4-[4-(5-Methyl-1H-pyrazol-3-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-2-ylsulfanyl]-phenyl}-benzamide

6A (184 mg, 2 equiv) was added to a suspension of K₂CO₃ (255 mg, 2.3equiv) in 5 mL DMF at rt. After 10 min., 1C (100 mg, 1 equiv) was addedas a 1 mL DMF solution. The reaction was stirred at 110° C. overnight,resulting in product formation as shown by LCMS. The reaction was thenextracted using EtOAc, and the combined organic phases were washed withwater and brine. The organic layer was dried with MgSO₄ thenconcentrated. The crude mixture was triturated with EtOAc to obtain 6B.MS: 442 [M+H]⁺; ¹H NMR (DMSO-d₆): 12.05 (s, 1H), 10.85 (s, 1H), 10.64(s, 1H), 8.00 (br. m, 5H), 7.45 (br. m, 6H), 7.23 (br. s, 1H), 6.59 (br.s, 1H), 5.8 (br. s, 1H) 2.2 (s, 1H).

1. A compound of Formula (I)

or pharmaceutically acceptable salts thereof, wherein: Q¹ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R¹ is H, —NR⁶C(═O)R⁷, —OR⁷, or —C(═O)NR⁷R⁸; Q² is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R² is H, alkyl, substituted alkyl, hydroxy (—OH), alkoxy, halogen, haloalkyl, haloalkoxy, oxo, aryloxy, arylalkyl, arylalkyloxy, alkanoyl, substituted alkanoyl, alkanoyloxy, amino, aminoalkyl, substituted aminoalkyl, alkylamino, substituted alkylamino, hydroxyalkyl, disubstituted amino, amide, substituted amide, carbamate, substituted carbamate, ureido, cyano, sulfonamide, substituted sulfonamide, alkylsulfone, heterocycloalkyl, substituted heterocycloalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, —NR⁶(C═O)R⁹, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaryloxy, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, heterocycle, substituted heterocycle, alkylcarbonyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, arylamino, arylalkylamino, alkanoylamino, arylamino, arylalkanoylamino, arylthio, arylalkylthio, arylsulfonyl, arylalkylsulfonyl, alkylsulfonyl, arylcarbonylamino, or alkylaminocarbonyl; R³, R⁴, and R⁵ are independently selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, alkanoyl, substituted alkanoyl, amino, aminoalkyl, substituted aminoalkyl, alkylamino, substituted alkylamino, amide, substituted amide, carbamate, ureido, cyano, sulfonamide, substituted sulfonamide, alkylsulfone, cycloalkyl, substituted cycloalkyl, nitro, thio, thioalkyl, alkylthio, disubstituted amino, alkylsulfonyl, alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, —NR⁶(C═O)R⁹, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and alkylcarbonyl. R⁶ is H, lower alkyl, or substituted lower alkyl; R⁷ and R⁸ are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, hetroalkynyl, or substituted heteroalkynyl; R⁹ is H, alkyl, substituted alkyl, alkoxy, aminoalkyl, substituted aminoalkyl, alkylamino, substituted alkylamino, aryl, or substituted aryl.
 2. A compound according to claim 1, wherein Q² is heteroaryl or substituted heteroaryl.
 3. A compound according to claim 1, wherein Q² is pyrazole, thiazole, or pyrimidine.
 4. A compound according to claim 1, wherein R² is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl.
 5. A compound according to claim 1, wherein Q¹ is aryl or substituted aryl.
 6. A compound according to claim 1, wherein Q¹ is phenyl or substituted phenyl.
 7. A compound according to claim 1, wherein R³, R⁴, and R⁵ are independently selected from H, alkyl, substituted alkyl, alkoxy, and halogen.
 8. A compound according to claim 1, wherein R⁷ and R⁸ are independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, or substituted cycloalkyl.
 9. A compound according to claim 1, wherein R¹ is —NR⁶C(═O)R⁷ and R² is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl.
 10. A compound according to claim 1, having the formula

or a pharmaceutically acceptable salt thereof, wherein: Q¹, R¹, R², R³, R⁴, R⁵ and R⁷ are as defined hereinabove.
 11. The compound according to claim 10, wherein Q¹ is aryl or substituted aryl.
 12. A compound according to claim 10, having the formula

or a pharmaceutically acceptable salt thereof, wherein: Q¹, R¹, R², R³, R⁴, and R⁵ are as defined hereinabove.
 13. A compound according to claim 12, wherein R¹ is —NR⁶C(═O)R⁷ and R² is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl.
 14. A pharmaceutical composition comprising a) at least one compound according to claim 1; b) optionally at least one pharmaceutically-acceptable carrier and/or diluent; and c) optionally at least one other anti-cancer agent
 15. A method for treating at least one proliferative disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound according claim 1; optionally administering either simultaneously or sequentially at least one other anti-cancer agent, and optionally administering either simultaneously or sequentially at least one other anti-cancer treatment.
 16. The method according to claim 15, wherein the proliferative disease is selected from cancer, bone disease, inflammatory disease, autoimmune disease, metabolic disease, viral disease, fungal disease, neurological and neurodegenerative disorders, Alzheimer's disease, allergies and asthma, cardiovascular disease, and hormone related disease.
 17. The method according to claim 15, wherein the proliferative disease is cancer.
 18. The method according to claim 17, wherein the patient is a human.
 19. The method according to claim 15, wherein the patient is a human.
 20. A compound according to claim 1 selected from (i) N-[4-({4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide; N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-{[3-(methyloxy)phenyl]sulfanyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine; N-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}sulfanyl)phenyl]acetamide; 3-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}sulfanyl)-N-methylbenzamide; N-(5-methyl-1H-pyrazol-3-yl)-2-(phenylsulfanyl)pyrrolo[2,1-][1,2,4]triazin-4-amine; and N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)sulfanyl)phenyl)benzamide; and (ii) a pharmaceutically acceptable salt thereof. 